Generation of T cell memory is a critical component of protective immunity. While memory T cells normally arise following priming of naove T cells with foreign antigen, a distinct pathway can also generate functional memory T cells - as a consequence of homeostatic proliferation in a lymphopenic environment. Study of memory T cells produced by homeostatic proliferation (HP memory cells) is relevant to understanding the essential requirements for memory T cell differentiation, and also for assessing the relevance of this alternative pathway in establishing protective immunity in immunocompromized individuals. Using mouse models, we recently showed that both conventional memory T cells (i.e. those generated through priming) and HP memory CD8 T cells offer similar protective immunity against a pathogen. However, while experimental models of lymphopenia are well studied, much less is known about HP memory cells produced during natural situations of lymphopenia (in the neonatal period and after acute infections). We explore this in three aims, studying: the function of HP memory CD8 T cells generated in natural lymphopenic environments (Aim 1): the presence and function of antigen specific endogenous HP memory CD8 T cells (Aim 2) and the role of neonatal lymphopenia and endogenous HP CD8 memory T cells in supporting immune reactivity of the young animals (Aim 3). The goal of these studies is to determine whether foreign antigen responsive HP memory CD8 T cells are generated during natural bouts of lymphopenia, and whether they contribute to the adaptive immune response. PUBLIC HEALTH RELEVENCE: Memory T cells are a critical element in immune protection against pathogens. Memory cells are generated as a consequence of immune priming, but are also generated during the response to immuno-deficiency, or lymphopenia, which occurs physiologically during development and also as a consequence of infections. The significance of the proposal is in learning how such homeostatic mechanisms may foster establishment of protective memory- like CD8 T cells system in immunocompromized individuals, including the very young.